Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally-occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally-occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting

Convergent Evidence from Mouse and Human Studies Suggests the Involvement of Zinc Finger Protein 326 Gene in Antidepressant Treatment Response

OBJECTIVES: The forced swim test (FST) is a commonly used model to predict antidepressant efficacy. Uncovering the genetic basis of the model may unravel the mechanism of antidepressant treatment. METHODS: FVB/NJ (FVB) and C57BL/6J (B6) were first identified as the response and non-response strains to fluoxetine (a serotonin-specific reuptake inhibitor antidepressant) treatment in the mouse FST. Simple-interval (SIM) and composite-interval (CIM) mappings were applied to map the quantitative trait loci (QTLs) of the anti-immobility effect of fluoxetine in FST (FST(FLX)) in 865 male B6×FVB-F2 mice. The brain mRNA expressions of the gene with the maximum QTL-linkage signal for FST(FLX) after the FST were compared between B6 and FVB mice and also compared between fluoxetine and saline treatment. The association of the variants in the human homologue of the mouse FST(FLX)-QTL gene with major depressive disorder (MDD) and antidepressant response were investigated in 1080 human subjects (MDD/control = 582/498). RESULTS: One linkage signal for FST(FLX)-QTL was detected at an intronic SNP (rs6215396) of the mouse Zfp326 gene (maximal CIM-LOD = 9.36). The Zfp326 mRNA expression in the FVB thalamus was significantly down-regulated by fluoxetine in the FST, and the higher FVB-to-B6 Zfp326 mRNA expressions in the frontal cortex, striatum and hypothalamus diminished after fluoxetine treatment. Two coding-synonymous SNPs (rs2816881 and rs10922744) in the human homologue of Zfp326, ZNF326, were significantly associated with the 8-week antidepressant treatment response in the MDD patients (Bonferroni-corrected p = 0.004-0.028). CONCLUSIONS: The findings suggest the involvement of the Zfp326 and ZNF326 genes in antidepressant treatment response

Strain-specific response to fluoxetine in mouse FST.

<p>Immobility time in the FST of B6 (1a), BALB (1b), FVB (1c), DBA (1d) and C3H (1e) mice after administration of different doses of fluoxetine. The FST was conducted 30 minutes after fluoxetine or saline injection (i.p.). “*” denotes a p-value lower than 0.05 compared with the saline group in the post hoc analysis. FST: forced swim test.</p

Mouse single nucleotide polymorphisms (SNPs) that were associated with immobility time in the FST after fluoxetine treatment (FST_FLX).

<p>SD: standard deviation; cM: centi-morgan; LOD: logarithm (base 10) of odds; LOD_(SIM): the LOD scores derived from simple interval mapping; LOD_(CIM): LOD scores derived from composite interval mapping;</p>a<p>The proportion of contribution the genetic polymorphism on the overall variation of the immobility time in FST after fluoxetine treatment.</p>b<p>P-value for one way analysis of variance.</p>c<p>The allele that shows significantly shorter immobility time in FST after fluoxetine treatment than the other allele.</p>d<p>The list of the gene located in 1 mega-bases from the SNP.</p

LOD scores for linkage for FST_FLX.

<p>The solid red line at LOD  = 3.33 and the blue dashed line at LOD  = 4.68 denote the genome-wide significance threshold for FST_FLX (SIM) and FST_FLX (CIM), respectively. The gray zone indicates the 2-LOD confidence interval. FST: forced swim test; FST_FLX: immobility in the mouse FST with fluoxetine treatment; LOD: logarithm of odds; SIM: simple interval mapping; CIM: composite interval mapping.</p

The association of mouse <i>Zfp326</i> function SNP with FST response to fluoxetine treatment.

<p>Genetic variations in <i>Zfp326</i>, rs33550587 (Asp494Gly) (4a) and rs13473815 (4b), are associated with the mouse response to fluoxetine in the FST. The B6×FVB-F2 mice were grouped according to genotype. * p<0.05; ^#p<0.0001. The digits in the bars represent the number of animals in each group. <i>Zfp326</i>: zinc finger protein 326 gene; SNP: single nucleotide polymorphism; FST: forced swim test.</p

Genotype and allele distribution of <i>ZNF326</i> polymorphisms in the controls, and in the patients with major depressive disorder and their responses to 8-weeks’ antidepressant treatment.

*<p>The P-value in boldface indicates the significance survived after correction for multiple comparisons (adjusted significant threshold with Bonferroni’s procedure: P<0.0125). “#” denotes the p-value obtained from Fisher exact test.</p